Biotherapeutic and Medicinal Sciences, Biogen, 225 Binney Street, Cambridge, MA 02142, United States.
Biotherapeutic and Medicinal Sciences, Biogen, 225 Binney Street, Cambridge, MA 02142, United States.
Bioorg Med Chem Lett. 2018 Jun 1;28(10):1964-1971. doi: 10.1016/j.bmcl.2018.03.032. Epub 2018 Mar 26.
Germinal center kinase-like kinase (GLK, also known as MAP4K3) has been hypothesized to have an effect on key cellular activities, including inflammatory responses. GLK is required for activation of protein kinase C-θ (PKCθ) in T cells. Controlling the activity of T helper cell responses could be valuable for the treatment of autoimmune diseases. This approach circumvents previous unsuccessful approaches to target PKCθ directly. The use of structure based drug design, aided by the first crystal structure of GLK, led to the discovery of several inhibitors that demonstrate potent inhibition of GLK biochemically and in relevant cell lines.
生殖中心激酶样激酶 (GLK，也称为 MAP4K3) 被认为对关键细胞活动有影响，包括炎症反应。GLK 是 T 细胞中蛋白激酶 C-θ (PKCθ) 激活所必需的。控制辅助性 T 细胞反应的活性对于治疗自身免疫性疾病可能是有价值的。这种方法避免了以前靶向 PKCθ 直接失败的方法。基于结构的药物设计的使用，在 GLK 的第一个晶体结构的帮助下，发现了几种抑制剂，这些抑制剂在生化和相关细胞系中都能有效地抑制 GLK。
